Dementia, myelopathy and neuropathy in acquired immunodeficiency syndrome (AIDS) and AIDS related complex (ARC) patients are distinctive neurological syndromes that are associated with infection of the central nervous system by human immunodeficiency virus (HIV). The aims of this interdisciplinary project are to develop clinically useful prodrugs for AIDS and ARC, which can cross the blood-brain barrier and exert antiviral activities against HIV after being regenerated to the parent drugs by cellular enzymes. Dihydronicotinic acid-nucleoside conjugates are the major class of proposed prodrugs. The pharmacokinetic aspects of the prodrugs will be studied in mice. The protein binding characteristics, bioavailability, and biotransformation of the prodrugs to the parent drugs and their metabolites will be determined. Pharmacokinetic parameters will be correlated with prodrug lipophilicity expressed as an octanol to water partition coefficient. The antiviral activity of the drugs in cells expressing the CD4 antigen will be determined. It will be particularly important to evaluate the new drugs for their activity and specificity against U937 monocytes since HIV-infected mononuclear inflammatory cells have been detected in AIDS patients with neurological illness. The behavior of the pro- and parent drug as substrates for purified enzymes that may be important in the bioactivation of nucleoside analogs (kinases, deaminases and polymerases) will be determined. In order to study the efficacy and transport of the proposed prodrugs in infected cells in the brain, a mouse retroviral model that causes neurological disease will be used. The efficacy of the prodrugs will be compared to the parent drug and the result will be correlated with the pharmacokinetic data. Additionally, in an effort to increase the bioavailability of antiviral drugs of known efficacy as well as to decrease the toxicity, we also propose to study the biochemical transformation of our newly discovered antiviral agents, 3'-azido-2',3'- dideoxyuridine (CS-87), 3'-azido-2',3'-dideoxycytidine (CS-91), and 3'-azido-2',3'-dideoxy-5-methylcytidine (CS-92) to 3'-azido-3'- deoxy-thymidine (AZT) in vitro as well as in vivo as a part of novel nucleoside prodrug development strategy utilizing cellular thymidylate synthase and 2'-deoxycytidine deaminase. The goals of these studies are to develop improved non-toxic anti- HIV prodrugs that are activated by specific cellular enzymes in virally infected cells.